A LECTIN-CONTRAST AGENT FOR MULTIMODALITY MOLECULAR IMAGING OF TUMOR ANGIOGENESIS

描述（由申请人提供）：本提案的主要目标是开发一种从头凝集素靶向成像探针，该探针可提高我们使用分子磁共振成像（MRI）对血管生成期间肿瘤血管中的结构和功能变化进行成像的能力。我们建议使用Bandeiraea Simplicifolia（GS-1）的凝集素开发一种双模态（MRI和光学）造影剂，该凝集素是一种非免疫来源的蛋白质，可与内皮细胞结合，在体内长达18小时而不会从肿瘤血管外渗。目标1专注于开发基于T1脂质体的凝集素靶向造影剂，而目标2专注于开发基于T2超顺磁性凝集素靶向纳米颗粒的造影剂。使用这些新的造影剂，我们打算在人转移性乳腺癌模型中表征伴随肿瘤进展的血管结构重塑。我们将使用高分辨率3D MRI在体内进行这项研究，并首次使用MR显微镜（MRI）进行体外研究，产生血管结构的第一个3D数字模型。这些新的造影剂上的荧光标记将使激光扫描共聚焦显微镜直接验证MRI数据成为可能。这些数据将促进我们对血管生成和图像对比度的基本机制的理解。它的低毒性，血管特异性和广泛的体内半衰期，可以使我们的凝集素靶向造影剂的一个宝贵的新工具，用于监测患者的抗血管生成治疗的疗效。该申请名为“A Lectin-Contrast Agent For Multimodality Molecular Imaging of Tumor Angiogenesis”，其重点是开发一种用于分子MRI的新型基于凝集素的造影剂，该造影剂通过Bandeiraea Simplicifolia凝集素对内皮细胞的亲和力优先靶向血管。我们打算合成和表征这种造影剂的T1和T2版本，并利用它们更好地了解肿瘤血管生成在人转移性乳腺癌异种移植模型中的作用。

DESCRIPTION (provided by applicant): The primary goal of this proposal is to develop a de novo lectin-targeted imaging probe that improves our ability to image the structural and functional changes in tumor blood vessels during angiogenesis, using molecular magnetic resonance imaging (MRI). We propose to develop a dual-modality (MRI and optical) contrast agent targeted to the lumen of blood vessels using the lectin from Bandeiraea Simplicifolia (GS-1), a protein of non-immune origin that binds to endothelial cells, for up to 18h in vivo without extravasating from tumor vessels. Aim 1 is focused on developing a T1 liposome-based lectin-targeted contrast agent, while Aim 2 focuses on developing a T2 superparamagnetic lectin-targeted nanoparticle based contrast agent. With these new contrast agents, we intend to characterize the remodeling of the vascular architecture that accompanies tumor progression, in a human metastatic breast cancer model. We will do this in vivo using high-resolution 3D MRI, and for the first time ex vivo using MR microscopy (}MRI), producing the very first 3D }digital casts} of the vessel architecture. The fluorescent tag on these new contrast agents will enable direct validation of the MRI data with laser scanning confocal microscopy. These data will promote our understanding of the basic mechanisms underlying angiogenesis and resulting image contrast. Its low toxicity, blood vessel specificity and extensive half-life in vivo, could make our lectin-targeted contrast agents an invaluable new tool for monitoring the efficacy of anti-angiogenic therapies in patients. The application titled "A Lectin-Contrast Agent For Multimodality Molecular Imaging of Tumor Angiogenesis" is centered on developing a novel lectin-based contrast agent for molecular MRI, which preferentially targets blood vessels via the affinity of the lectin from Bandeiraea Simplicifolia for endothelial cells. We intend to synthesize and characterize, both T1 and T2 versions of this contrast agent, and employ them to better understand the role of tumor angiogenesis in a human metastatic breast cancer xenograft model.